Use of organic compounds

ABSTRACT

The invention relates to the use of a hypolipidemic agent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or delay of the progression to overt diabetes, especially type 2, prevention or reduction of microvascular complications (eg, retinopathy, neurophathy, nephropathy), prevention or reduction of excessive cardiovascular morbidity (eg, myocardial infarction, arterial occlusive disease, atherosclerosis and stroke) and cardiovascular mortality, prevention of cancer and reduction of cancer deaths. Additionally, the invention relates to the use of a treatment for diseases and conditions that are associated with IGM, IGT or IFG.

[0001] Impaired Glucose Metabolism (IGM) is defined by blood glucoselevels that are above the normal range but are not high enough to meetthe diagnostic criteria for type 2 diabetes mellitus. The incidence ofIGM varies from country to country, but usually occurs 2-3 times morefrequently than overt diabetes. Until recently, individuals with IGMwere felt to be pre-diabetics, but data from several epidemiologicstudies argue that subjects with IGM are heterogeneous with respect totheir risk of diabetes and their risk of cardiovascular morbidity andmortality. The data suggest that subjects with IGM, in particular IGT,do not always develop diabetes, but whether they are diabetic or not,they are, nonetheless, at high risk for cardiovascular morbidity andmortality.

[0002] Among subjects with IGM, about 58% have Impaired GlucoseTolerance (IGT), another 29% have Impaired Fasting Glucose (IFG), and13% have both abnormalities (IFG/IGT). IGT is characterized by elevatedpostprandial (post-meal) hyperglycemia while IFG has been defined by theADA (see Table below) on the basis of fasting glycemic values.

[0003] The categories of Normal Glucose Tolerance (NGT), IGM and type 2diabetes mellitus were defined by the ADA in 1997 as follows: Type 2Diabetes NGT IGM mellitus IFG FPG level <6.1 mmol/L   6.1-7 mmol/L   >7mmol/L (<110 mg/dl) (110-126 mg/dl)  >126 mg/dl) And and/or or IGT 2 hpostprandial <7.8 mmol/l 7.8-11.1 mmol/L >11.1 mmol/L glucose (<140mg/dl) (140-220 mg/dl) (>200 mg/dl) level (75 g OGTT*⁾)

[0004] Individuals with IGM, especially those with the subcategory IFG,are known to have a significantly higher rate of progression to diabetesthan normoglycemic individuals and are known to be high atcardiovascular risk, especiallly if they develop diabetes.Interestingly, subjects with IGM, more specifically those with thesubcategory IGT, have a high incidence of cancer, cardiovasculardiseases and mortality even if they never develop diabetes. Therefore,IGM and more specifically, the subgroup IFG, appears to be at highcardiovascular risk, especially after patients become overtly diabetic.IGT, on the other hand, is associated with a high risk for cancer,cardiovascular disease and mortality in nondiabetics and diabetics. Theincreased risk associated with IGT is independent of all other knowncardiovascular risk factors including age, sex, hypertension, low HDLand high LDL cholesterol levels [Lancet 1999; 354: 617-621].

[0005] One mechanism through which IGM, and more specifically, IGT, hasbeen linked to micro- and macroangiopathic complications in the absenceof the abnormal FPG characteristic of diabetics, is postprandialhyperglycemia. Isolated postprandial hyperglycemia, even innondiabetics, has been shown to reduce the natural free-radical trappingagents (TRAP) that are present in serum. Decreasing the level of TRAPhas been shown, under experimental conditions, to be associated with anincrease in free radical formation and increased oxidative stress. Thesefree radicals have been implicated in the pathological microvascular andmacrovascular changes associated with atherosclerosis, cardiovascularmorbidity and mortality, and cancer [Ceriello, A, Diabetic Medicine 15:188-193, 1998]. The decrease of natural antioxidants like TRAP duringpostprandial hyperglycemia may explain the increased cardiovascular riskin subjects with IGM, and specifically IGT, that do not developdiabetes. The fact that IGT is an independent risk factor innon-diabetics as well as diabetics justifies it as a new indication,separate from diabetes, for prevention and treatment of cardiovascularmorbidity and mortality as well as cancer.

[0006] IGM is associated with following potential diseases orconditions: 1.) progression to overt diabetes mellitus type 2 (Code250.2 of the International Classification of Diseases 9^(th)version=ICD-9 Code 250.2) [Diabetes Research and Clinical Practice 1998;40: S1-S2]; 2.) increased microvascular complications of diabetesespecially retinopathy and other ophthalmic complications of diabetes(ICD-9 code 250.5), nephropathy (ICD-9 code 250.4), neuropathy (ICD-9code 250.6) [Diabetes Care 2000; 23: 1113-1118], and peripheralangiopathy or gangrene (ICD-9 code 250.7); 3.) increased cardiovascularmorbidity (ICD-9 codes 410-414) especially myocardial infarctions (ICD-9code 410), coronary heart disease or atherosclerosis (ICD-9 code 414)and other acute and subacute forms of coronary ischemia (ICD-9 code411); 4.) excess cerebrovascular diseases like stroke (ICD-9 codes430-438) [Circulation 1998; 98: 2513-2519]); 5.) increasedcardiovascular mortality (ICD-9 codes 390-459) [Lancet 1999; 354:617-621], and sudden death (ICD-9 code 798.1); 6.) higher incidences andmortality rates of malignant neoplasms (ICD-9 codes 140-208) [Am JEpidemiol. 1990; 131: 254-262, Diabetologia 1999; 42: 1050-1054]. Othermetabolic disturbances that are associated with IGM include dyslipidemia(ICD-9 code 272), hyperuricemia (ICD-9 code 790.6) as well ashypertension (ICD-9 codes 401-404) and angina pectoris (ICD-9 code413.9) [Ann Int Med 1998; 128: 524-533].

[0007] Clearly, the broad spectrum of diseases and conditions that arelinked to IGM, and especially IGT, represents an area of tremendousmedical need. Many of the same diseases and conditions have beenassociated with both IGM and diabetes, but only recently has it beenpossible to identify that that the nondiabetic population that has IGM,and especially IGT, should be an indication for prevention andtreatment. Accordingly, in subjects with IGM and especially IGT and/orIFG, the restoration of early phase insulin secretion and/or thereduction of prandial hyperglycemia should help to prevent or delay theprogression to overt diabetes and to prevent or reduce microvascularcomplications associated with diabetes by preventing the development ofthe overt diabetes. In addition, in individuals with IGM and especiallythose with IGT and/or IFG, the restoration of early phase insulinsecretion and/or reduction of postprandial hyperglycemia should alsoprevent or reduce the excessive cardiovascular morbidity and mortality,and prevent cancer or reduce its mortality in individuals.

[0008] Thus the stage between normoglycemia and type 2 diabetesmellitus, especially the glycemic stage, is becoming of major interestand there is a strong need for a method to inhibit or delay theprogression to type 2 diabetes mellitus, and also the variety ofcardiovascular and microvascular conditions and diseases as well ascancer that have been associated with IGM and especially IFG and/or IGT.

[0009] It has unexpectedly been found that hypoglycemic agents such asinsulin secretion enhancers can be used to prevent or delay theprogression to overt diabetes, to reduce microvascular complications ofdiabetes, to reduce vascular, especially cardiovascular, mortality andmorbidity, especially cardiovascular morbidity and mortality, and toreduce increased mortality related to cancer in individuals with IGTand/or IFG.

[0010] Hypoglycemic agents comprise, for example, an insulin secretionenhancer or an insulin sensitivity enhancer (insulin resistancedeblocker) or insulin of, if appropriate, in each case apharmaceutically acceptable salt thereof.

[0011] Insulin secretion enhancers are active ingredients that have theproperty to promote the secretion of insulin from pancreatic β-cells.

[0012] An insulin secretion enhancer (also called insulin secretogogueand insulinotropic agent) is, for example, a shortacting or along-acting hypoglycemic agent.

[0013] A short-acting hypoglycemic is, for example, a phenylacetic acidderivative, furthermore gliquidone.

[0014] A corresponding phenylalanine derivative is, for example,nateglinide [N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine](cf. EP 196222 and EP 526171) of the formula

[0015] and repaglinide[(S)-2-ethoxy4-{2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl}benzoicacid]; and in free form or, if appropriate, in each case apharmaceutically acceptable salt thereof.

[0016] The term nateglinide likewise comprises crystal modificationssuch as disclosed in EP 0526171 B1 or U.S. Pat. No. 5,488,510,respectively, the subject matter of which, especially with respect tothe identification, manufacture and characterization of crystalmodifications, is herewith incorporated by reference to thisapplication, especially the subject matter of claims 8 to 10 of saidU.S. patent (referring to H-form crystal modification) as well as thecorresponding references to the B-type crystal modification in EP 196222B1 the subject matter of which, especially with respect to theidentification, manufacture and characterization of the B-form crystalmodification. Preferably, in the present invention, the B- or H-type,more preferably the H-type, is used.

[0017] A longacting hypoglycemic is, for example, a biguanide derivativeor a sulphonyl urea derivative.

[0018] An approriate biguanide is, for example, metformin or, ifappropriate, a pharmaceutically acceptable salt thereof, especially thehydrochloride thereof.

[0019] Examples of sulfonylurea derivatives (SU) are, especially thosewhich promote the secretion of insulin from pancreatic β-cells bytransmitting signals of insulin secretion via SU receptors in the cellmembrane, including (but are not limited to) tolbutamide;chlorpropamide; tolazamide; acetohexamide;4-chloro-N-[(1-pyrolidinylamino)carbonyl]-benzensulfonamide(glycopyramide); glibenclamide (glyburide); gliclazide;1-butyl-3-metanilylurea; carbutamide; glibonuride; glipizide;gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide;glymidine; glypinamide; phenbutamide; and tolylcyclamide, or, ifappropriate, in each case a pharmaceutically acceptable salt thereof.

[0020] Insulin secretion enhancers furthermore include therepresentatives of the new generation of SUs such as calcium(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinlycarbonyl)-propionatedihydrate (KAD-1229) and glimepiride (Hoe 490); and in free orpharmaceutically acceptable salt form.

[0021] Insulin secretion enhancers likewise include DPP-IV inhibitors,GLP1 and GLP1 agonists.

[0022] DPP-IV is a serine protease and catalyses cleavage of N-terminalXaa-Pro or XaaAla dipeptide residues omcluding glucagon-like protein-1(GLP-1). Corresponding inhibitors of DPP-IV increase circulatingconcentrations of GLP-1 and therefore increasing insulin secretion.

[0023] Representatives of DPP-IV inhibitors are described in WO98/19998and WO00/34241. Preferred is1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2(S)-cyano-pyrrolidinedihydrochloride (cf. example 3 of WO98/19998) and(S)1-[(3-hydroxy-1-adamantyl)amino]-acetyl-2-cyano-pyrrolidine (cf.example 1 of W00/34241).

[0024] GLP-1 and GLP-1 agonists likewise enhance insulin secretion.

[0025] A preferred insulin secretion enhancer is repaglinide andmetformin, most preferred is nateglinide.

[0026] An insulin sensitivity enhancer restores impaired insulinreceptor function to reduce insulin resistance and consequently enhancethe insulin sensitivity.

[0027] An appropriate insulin sensitivity enhancer is, for example, anappropriate hypoglycemic thiazolidinedione derivative (glitazone).

[0028] An appropriate glitazone is, for example,(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione(englitazone),5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione(darglitazone),5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione(ciglitazone),5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(DRF2189),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione(BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637),bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-thiazolidine-2,4-dione(AD-5075),5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione(DN-108)5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione,5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione,5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione,5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(rosiglitazone),5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione(pioglitazone),5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}-thiazolidine-2,4-dione(troglitazone),5-[6-(2-fluoro-benzyloxy)naphthalen-2-ylmethyl]-thiazolidine-2,4-dione(MCC555),5-{[2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione(T-174) and5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide(KRP297). Preferred are pioglitazone, rosiglitazone and troglitazone.

[0029] The structure of the active agents identified by generic ortradenames may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference. Any person skilled in theart is fully enabled to identify the active agents and, based on thesereferences, likewise enabled to manufacture and test the pharmaceuticalindications and properties in standard test models, both in vitro and invivo.

[0030] Favorable effects can be verified that confirm that hypoglycemicagents such as insulin enhancers can restore early phase insulinsecretion and reduce post-prandial glucose levels in subjects with IGM.A multi-center, double-blind, parallel group, randomized study can beconducted in subjects with IGM in order to evaluate the incidence ofconfirmed hypoglycemia and the effects on prandial glucose associatedwith the administration of nateglinide 30 mg, 60 mg or 120 mg or placebobefore each main meal during 8 weeks of treatment. Subjects are selectedon the basis of a 2-hour plasma glucose value after a 75 g oral glucosetolerance test (OGTT) and patients essentially meeting the followingadditional inclusion criteria are included in the study:

[0031] two-hour glycemia post-OGTT between 7.8 to 11.1 mmol/L (one OGTTto be performed during the year before entering the study, the second tobe performed within two weeks prior entering the study);

[0032] FPG<7 mmol/L;

[0033] patients are to have a body mass index (BMI) between 20-32 kg/m2;

[0034] patients are to maintain prior diet during the full course ofstudy;

[0035] males, non-fertile females, females of child-bearing potentialusing a medically approved birth control method are included;

[0036] the use of other antidiabetics during the trial is not permitted.

[0037] Corresponding dosages of e.g. nateglinide are administered with alarge glass of water 2 (BID), 3 (TID) or 4 (QID) times daily dependingon the number of main meals (breakfast, lunch, snack, dinner). The firstdose is to be given with the first main meal (standardized meal i.e. 55%carbohydrates, 25% fat and 20% protein). Visits are scheduled to beperformed at weeks 0, 2, 4 and 8 and the patients are to be fasted forat least 7 hours. All blood samples for laboratory evaluations are drawnbetween 07.00 and 10.00 a.m. HbA1c is to be measured at baseline andafter 8 weeks of treatment (fasting glucose and fructosamine). Samplesof blood are to be drawn at 10, 20, 20, 60, 120, and 180 minutes afterdrug administration (time 0) and the glucose and insulin levels to bemeasured. At weeks 0 and 8 visits, patients complete a standard mealchallenge containing approximately 500 kcal and measurements of insulinand glucose will be performed.

[0038] The findings from analyses of all obtained data in such a studyclearly revealed that 2 hour prandial glucose levels, HBA1c andfructosamine levels were surprisingly and significantly reduced, thatearly phase insulin secretion was restored, and that nateglinide couldprevent or delay the progression to type 2 diabetes mellitus. Withlonger treatment and follow-up, conditions and diseases associated withIGM could be prevented or reduced.

[0039] This type of study in individuals with IGM and particularly IFGand IGTdiffers from those in diabetics since the subjects have normalFPG and are nondiabetics or pre-diabetics.

[0040] Surprisingly, hypoglycemic agents as well as a combination ofhypoglycemic agents can be used in subjects with IGM, especially IFGand/or IGT, for the prevention or delay of progression to overt diabetesmellitus type 2; for the prevention, reduction or delay in onset of acondition selected from the group consisting of increased microvascularcomplications; increased cardiovascular morbidity; excesscerebrovascular diseases; increased cardiovascular mortality and suddendeath; higher incidences and mortality rates of malignant neoplasms; andother metabolic disturbances that are associated with IGM.

[0041] Furthermore, hypoglycemic agents as well as a combination ofhypoglycemic agents can be used in subjects with IGM, especially IFGand/or IGT, for the prevention, reduction or delay in onset of acondition selected from the group e.g. consisting of retinopathy, otherophthalmic complications of diabetes, nephropathy, neuropathy,peripheral angiopathy, peripheral angiopathy, gangrene, myocardialinfarctions, coronary heart disease, atherosclerosis, other acute andsubacute forms of coronary ischemia, stroke, dyslipidemia,hyperuricemia, hypertension, angina pectoris, microangiopathic changesthat result in amputation, cancer, cancer deaths, obesity, uricemia,insulin resistance, arterial occlusive disease, and atherosclerosis.

[0042] According to the present invention, hypoglycemic agents can beused in subjects with IGM, especially with IFG and/or IGT, to prevent ordelay the progression to overt diabetes, to reduce microvascularcomplications of diabetes, to reduce vascular, especiallycardiovascular, mortality and morbidity, especially cardiovascularmorbidity and mortality, and to reduce increased mortality related tocancer in individuals with IGT.

[0043] Accordingly, the present invention relates to a method insubjects with IGM, especially IFG and/or IGT, for the prevention ordelay of progression to overt diabetes mellitus type 2; for theprevention, reduction or delay in onset of a condition selected from thegroup consisting of increased microvascular complications; increasedcardiovascular morbidity; excess cerebrovascular diseases; increasedcardiovascular mortality and sudden death; higher incidences andmortality rates of malignant neoplasms; and other metabolic disturbancesthat are associated with IGM.

[0044] Especially, the present invention relates to a method used insubjects with IGM, especially IFG and/or IGT, for the prevention,reduction or delay in onset of a condition selected from the group e.g.consisting of retinopathy, other ophthalmic complications of diabetes,nephropathy, neuropathy, peripheral angiopathy, peripheral angiopathygangrene, myocardial infarctions, coronary heart disease,atherosclerosis, other acute and subacute forms of coronary ischemia,stroke, dyslipidemia, hyperuricemia, hypertension, angina pectoris,microangiopathic changes that result in amputation, cancer, cancerdeaths, obesity, uricemia, insulin resistance, arterial occlusivedisease, and atherosclerosis.

[0045] Accordingly, the present invention relates to a method ofprevention or delay of the progression to overt diabetes, especiallytype 2 (ICD-9 Code 250.2), prevention or reduction of microvascularcomplications like retinopathy (ICD-9 code 250.5), neurophathy (ICD-9code 250.6), nephropathy (ICD-9 code 250.4) and peripheral angiopathy organgrene (ICD-9 code 250.7), later termed “microvascular complications”in subjects with IGM, especially IFG and IGT. Further the presentinvention relates to a method to prevent or reduce conditions ofexcessive cardiovascular morbidity (ICD-9 codes 410-414), e.g.myocardial infarction (ICD-9 code 410), arterial occlusive disease,atherosclerosis and other acute and subacute forms of coronary ischemia(ICD-9 code 411-414), later termed “cardiovascular morbidity”; toprevent, reduce, or delay the onset of excess cerebrovascular diseaseslike stroke (ICD-9 codes 430-438); to reduce increased cardiovascularmortality (ICD-9 codes 390-459) and sudden death (ICD-9 code 798.1); toprevent the development of cancer (ICD-9 codes 140-208) and to reducecancer deaths, in each case, in subjects with IGM, especially IFG andIGT. The method further relates to a method of prevention or reductionof other metabolic disturbances that are associated with IGM includinghyperglycemia (including isolated postprandial hyperglycemia),dyslipidemia (ICD-9 code 272), hyperuricemia (ICD-9 code 790.6) as wellas hypertension (ICD-9 codes 401-404) and angina pectoris (ICD-9 code413.9), in each case, in subjects with IGM, especially IFG and IGT.

[0046] The codes identified hereinbefore and herafter according to theInternational Classification of Diseases 9^(th) version and thecorresponding definitions allocated thereto are herewith incorporated byreference and likewise form part of the present invention.

[0047] The induction by hypoglycemic agents, in particular of earlyphase secretion, is rapidly reversible and the reduction of postprandialglucose levels is favorable for prevention or treatment in thisindication.

[0048] The method comprises administering to a subject in need thereofan effective amount of hypoglycemic agents such as an insulin secretionenhancer or a pharmaceutically acceptable salt thereof. A subject inneed of such method is a warm-blooded animal including man.

[0049] The present invention also relates to a method to be used insubjects with IGM, and especially IFG and/or IGT, and associateddiseases and conditions such as isolated prandial hyperglycemia,prevention or delay of the progression to overt diabetes, especiallytype 2, prevention reduction, or delay the onset of microvascularcomplications, prevention or reduction of gangrene or microangiopathicchanges that result in amputation, prevention or reduction of excessivecardiovascular morbidity and cardiovascular mortality, prevention ofcancer and reduction of cancer deaths.

[0050] The present invention likewise relates to a method of treatmentof conditions and diseases associated with IGM and especially IFG and/orIGT (including isolated prandial hyperglycemia) including obesity,increased age, diabetes during pregnancy, dyslipidemia, high bloodpressure, uricemia, insulin resistance, arterial occlusive disease,atherosclerosis, retinopathy, nephropathy, angina pectoris, myocardialinfarction, and stroke.

[0051] Preferably, said preventions should be effected in individualswith glucose levels in the ranges that have been proven in largeepidemiologic studies to confer increased cardiovascular, microvascularand cancer risk. These levels include levels of plasma glucose ≧7.8mmol/L mmol/L after an OGTT or casual glucose evaluation and/or fastingplasma glucose in the IFG range (fasting plasma glucose between 6.1 and7 mmol/l). As new epidemiologic data become available to lower theglycemic levels that are incontrovertibly linked to the above-mentionedrisks, or as the international standards for defining the IGT and IFGrisk groups are changed, the use of the invention is also warranted fortreatment of the groups at risk.

[0052] The present invention also relates to a method to be used insubjects with IFG comprising administering to a subject in need thereofa therapeutically effective amount of a DPP-IV inhibitor.

[0053] The present invention relates to the use of a hypoglycemic agentor a pharmaceutically acceptable salt thereof for the manufacture of amedicament in subjects with IGM, especially IFG and/or IGT, for theprevention or delay of progression to overt diabetes mellitus type 2;for the prevention, reduction or delay in onset of a condition selectedfrom the group consisting of increased microvascular complications;increased cardiovascular morbidity; excess cerebrovascular diseases;increased cardiovascular mortality and sudden death; higher incidencesand mortality rates of malignant neoplasms; and other metabolicdisturbances that are associated with IGM.

[0054] The present invention relates to the use of an insulin secretionenhancer or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the prevention or delay of theprogression to overt diabetes, especially type 2, prevention orreduction of microvascular complications, prevention or reduction ofexcessive cardiovascular morbidity and cardiovascular mortality,prevention of cancer and reduction of cancer deaths.

[0055] The present invention relates to the use of an insulin secretionenhancer or a pharmaceutically acceptable salt for the manufacture of amedicament in subjects with IGM, and especially IFG and/or IGT, andassociated diseases and conditions such as isolated prandialhyperglycemia for the following: prevention or delay of the progressionto overt diabetes, especially type 2, prevention or reduction ofmicrovascular complications, prevention or reduction of excessivecardiovascular morbidity and cardiovascular mortality, prevention ofcancer and reduction of cancer deaths.

[0056] The present invention relates to a pharmaceutical composition insubjects with IGM, especially IFG and/or IGT, for the prevention ordelay of progression to overt diabetes mellitus type 2; for theprevention, reduction or delay in onset of a condition selected from thegroup consisting of increased microvascular complications; increasedcardiovascular morbidity; excess cerebrovascular diseases; increasedcardiovascular mortality and sudden death; higher incidences andmortality rates of malignant neoplasms; and other metabolic disturbancesthat are associated with IGM; comprising a hypoglycemic agent or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

[0057] The present invention relates to a pharmaceutical composition forthe prevention or delay of the progression to overt diabetes, especiallytype 2, prevention or reduction of microvascular complications,prevention or reduction of excessive cardiovascular morbidity andcardiovascular mortality, prevention of cancer and reduction of cancerdeaths, comprising an insulin secretion enhancers or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

[0058] The present invention relates to a pharmaceutical composition insubjects with IGM, and especially IFG and/or IGT and associated diseasesand conditions such as isolated prandial hyperglycemia for thefollowing: prevention or delay of the progression to overt diabetes,especially type 2, prevention or reduction of microvascularcomplications, prevention or reduction of excessive cardiovascularmorbidity and cardiovascular mortality, prevention of cancer andreduction of cancer deaths.

[0059] The corresponding active ingredient or a pharmaceuticallyacceptable salt thereof may also be used in form of a hydrate or includeother solvents used for crystallization.

[0060] Furthermore, the present invention relates to the combinationsuch as a combined preparation or pharmaceutical composition,respectively, comprising at least one insulin secretion enhancer and altleast one insulin sensitiser; or at least two insulin secretionenhancers; or at least two insulin sensitisers; to be used in subjectswith IGM, especially IFG and/or IGT, for the prevention or delay ofprogression to overt diabetes mellitus type 2; for the prevention,reduction or delay in onset of a condition selected from the groupconsisting of increased microvascular complications; increasedcardiovascular morbidity; excess cerebrovascular diseases; increasedcardiovascular mortality and sudden death; higher incidences andmortality rates of malignant neoplasms; and other metabolic disturbancesthat are associated with IGM.

[0061] Further benefits when applying the combination of the presentinvention are that lower doses of the individual drugs to be combinedaccording to the present invention can be used to reduce the dosage, forexample, that the dosages need not only often be smaller but are alsoapplied less frequently, or can be used in order to diminish theincidence of side effects. This is in accordance with the desires andrequirements of the patients to be treated.

[0062] Preferably, the jointly therapeutically effective amounts of theactive agents according to the combination of the present invention canbe administered simultaneously or sequentially in any order, separatelyor in a fixed combination.

[0063] The term “therapeutically effective amount” shall mean thatamount of a drug or combination that will elicit the biological ormedical response needed to achieve the therapeutic effect as specifiedaccording to the present invention in the warm-blooded animal, includingman. A “therapeutically effective amount” can be administered whenadministering a single hypoglycemic agent and also in both a fixed orfree combination of hypoglycemic agents. A “jointly effective amount” ina combination according to the present invention shall also include anon-effective amount of at least one of the agents to be combined, ifthe overall effect can be achieved by the combined administration of the(fixed or free) combination.

[0064] The pharmaceutical composition according to the present inventionas described hereinbefore and hereinafter may be used for simultaneoususe or sequential use in any order, for separate use or as a fixedcombination.

[0065] Preferred components for a combination according to the presentinvention preferably those that are designated as preferred hypoglycemicagents, that are most preferably selected from nateglinide, repaglinide,metformin, pioglitazone, rosiglitazone, troglitazone,1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2(S)-cyano-pyrrolidine,and (S)1-[(3-hydroxy-1-adamantyl)amino]-acetyl-2-cyano-pyrrolidine, or,if appropriate, in each case, a pharmaceutically acceptable saltthereof.

[0066] In a variation thereof, the present invention likewise relates toa “kit-of-parts”, for example, in the sense that the components to becombined according to the present invention can be dosed independentlyor by use of different fixed combinations with distinguished amounts ofthe components, i.e. simultaneously or at different time points. Theparts of the kit of parts can then e.g. be administered simultaneouslyor chronologically staggered, that is at different time points and withequal or different time intervals for any part of the kit of parts.Preferably, the time intervals are chosen such that the effect on thetreated disease or condition in the combined use of the parts is largerthan the effect that would be obtained by use of only any one of thecomponents.

[0067] The invention furthermore relates to a commercial packagecomprising the combination according to the present invention togetherwith instructions for simultaneous, separate or sequential use.

[0068] The compounds to be combined can be present as pharmaceuticallyacceptable salts. If these compounds have, for example, at least onebasic center, they can form acid addition salts. Corresponding acidaddition salts can also be formed having, if desired, an additionallypresent basic center. The compounds having an acid group (for exampleCOOH) can also form salts with bases.

[0069] Pharmaceutically acceptable salts e.g. of nateglinide are, forexample, salts formed with bases, namely cationic salts such as alkaliand alkaline earth metal salts, as well as ammonium salts.

[0070] The pharmaceutical compositions according to the invention can beprepared in a manner known per se and are those suitable for enteral,such as oral or rectal, and parenteral administration to mammals(warm-blooded animals), including man, comprising a therapeuticallyeffective amount of the pharmacologically active compound, alone or incombination with one or more pharmaceutically acceptable carries,especially suitable for enteral or parenteral application.

[0071] The novel pharmaceutical preparations contain, for example, fromabout 10% to about 100%, preferably 80%, preferably from about 20% toabout 60%, of the active ingredient. Pharmaceutical preparationsaccording to the invention for enteral or parenteral administration are,for example, those in unit dose forms, such as sugar-coated tablets,tablets, capsules or suppositories, and furthermore ampoules. These areprepared in a manner known per se, for example by means of conventionalmixing, granulating, sugar-coating, dissolving or lyophilizingprocesses. Thus, pharmaceutical preparations for oral use can beobtained by combining the active ingredient with solid carriers, ifdesired granulating a mixture obtained, and processing the mixture orgranules, if desired or necessary, after addition of suitable excipientsto give tablets or sugar-coated tablet cores.

[0072] The doses for hypoglycemic agents for use according to thepresent invention may, for example, be those that are being used foragents that have already been launched. For example, tablets ofrepaglinide in doses of 0.5 mg, 1 mg or 2 mg of the active ingredient ortablets of metformin in doses of 500 mg or 850 mg of the activeingredient may be taken Likewise these doses may also be used for theagents to be combined combination according to the present invention. Aperson skilled in the art is fully enabled, based on his knowledge, todetermine the specific doses for the specific hypolipidemic agentswhether taken alone or in combination.

[0073] Nateglinide (I) is preferably administered to the warm-bloodedanimal in a dosage in the range of about 5 to 1200, more preferably 25to 800, mg/day, when the warm-blooded animal is a human of about 70 kgbody weight. Preferred dosages contain 30 mg, 60 mg or 120 mg ofnateglinde to be administered preferably before the main meals.Depending on the number of main meals the dose regimen are two times aday (BID) or three times a day (TID) or four times a day (QID).

[0074] The following Examples illustrate the invention described above;they are not, however, intended to limit the scope of the invention inany way.

EXAMPLE 1 Tablets of Nateglinide (I)

[0075] 216,000 tablets, each which contain 120 mg of nateglinide (I) areprepared as follows: Composition: nateglinide (I) 12.960 kg lactose, NF30.564 kg microcrystalline cellulose, NF 15.336 kg povidone, USP  2.592kg croscarmellose sodium, NF  3.974 kg colloidal silicon dioxide, NF 1.382 kg magnesium stearate, NF  1.231 kg coating: opadry yellow  1.944kg purified water, USP* Q.S.

[0076] Preparation process: The microcrystalline cellulose, povidone,part of the croscarmellose sodium, nateglinide (I) and lactose are mixedin a high shear mixer and afterwards granulated using purified water.The wet granules are dried in a fluid bed dryer and passed through ascreen. The colloidal silicon dioxide and the rest of the croscarmellosesodium are mixed, passed through a screen and blended with the driedgranules in a V-blender. The magnesium stearate is passed through ascreen, blended with the blend from the V-blender and afterwards thetotal mixture is compressed to tablets. The opadry yellow is suspendedin purified water and the tablets are coated with the coatingsuspension.

EXAMPLE 2 Galenic Formulation of Nateglinide (I) No. 1

[0077] intra-granular: nateglinide (I) 120 mg lactose monohydrate 283 mgmicrocrystalline cellulose 142 mg povidone  24 mg croscarmellose sodium 24 mg extra-granular: magnesium stearate  7 mg opadry white  20 mg

EXAMPLE 3 Galenic Formulation of Nateglinide (I) No. 2

[0078] intra-granular: nateglinide (I)  120 mg lactose monohydrate  283mg microcrystalline cellulose  142 mg povidone   24 mg croscarmellosesodium   24 mg extra-granular: croscarmellose sodium 12.8 mg magnesiumstearate 11.4 mg opadry yellow 18.0 mg colloidal silicon dioxide 12.8 mg

EXAMPLE 4 Tablets of Nateglinide

[0079] 108,000 tablets, each which contain 120 mg of nateglinide areprepared as follows: Composition: nateglinide 12.960 kg lactose, NF30.564 kg microcrystalline cellulose, NF 15.336 kg povidone, USP  2.592kg croscarmellose sodium, NF  3.974 kg colloidal silicon dioxide, NF 1.382 kg magnesium stearate, NF  1.231 kg coating: opadry yellow  1.944kg purified water, USP* Q.S.

[0080] Preparation Process: The microcrystalline cellulose, povidone, aportion of the croscarmellose sodium, nateglinide and lactose aregranulated in a collette gral granulator with the addition of purifiedwater. The wet granules are dried in a fluid bed dryer and passedthrough a screen. The colloidal silicon dioxide and the rest of thecroscarmellose sodium are mixed, passed through a screen and blendedwith the dried granules in a V-blender. The magnesium stearate is passedthrough a screen, blended with the blend from the V-blender andafterwards the total mixture is compressed to tablets. The opadry yellowis suspended in purified water and the tablets are coated with thecoating suspension. Variants of this process include adding thecolloidal silica and the remaining croscarmellose sodium to the secondgranulator load after drying, then screening together; and combining asmany as 3 granulator/drier loads per batch.

EXAMPLE 5 Pharmaceutical Composition of Nateglinide (120 mg)

[0081] nateglinide  120 mg lactose monohydrate  283 mg microcrystallinecellulose  142 mg Povidone   24 mg croscarmellose sodium 36.8 mgmagnesium stearate 11.4 mg opadry yellow 18.0 mg colloidal silicondioxide 12.8 mg

1. A method for treating or preventing conditions or diseases associatedwith IGT or IFG comprising administering repaglinide or apharmaceutically acceptable salt thereof to subjects in need thereof. 2.The method of claim 1 for the prevention or delay of progression toovert diabetes mellitus type 2; for the prevention, reduction or delayin onset of a condition selected from the group consisting of increasedmicrovascular complications; increased cardiovascular morbidity; excesscerebrovascular diseases; increased cardiovascular mortality and suddendeath; higher incidences and mortality rates of malignant neoplasms; andother metabolic disturbances that are associated with IGM.
 3. The methodof claim 1 for the prevention of cancer and reduction of cancer deaths.4. The method of claim 1 for the prevention, reduction or delay in onsetof a condition selected from the group e.g. consisting of retinopathy,other ophthalmic complications of diabetes, nephropathy, neuropathy,peripheral angiopathy, peripheral angiopathy or gangrene, myocardialinfarctions, coronary heart disease, atherosclerosis, other acute andsubacute forms of coronary ischemia, stroke, dyslipidemia,hyperuricemia, hypertension, angina pectoris, microangiopathic changesthat result in amputation, cancer, cancer deaths, obesity, uricemia,insulin resistance, arterial occlusive disease, and atherosclerosis. 5.The method of claim 1 for the treatment of diseases or conditionsassociated with isolated prandial hyperglycemia and/or IFG.
 6. Themethod of claim 1 for the prevention of diseases or conditionsassociated with IGT in subjects with prandial glucose excursions having2 hour plasma glucose values between 7.8 to 11.1 mmol/L after an OGTT orcasual glucose test.
 7. (canceled)
 8. (canceled)
 9. (canceled) 10.(canceled)
 11. The method of claim 5 wherein the disease and conditionassociated with isolated prandial hyperglycemia and/or IFG is selectedfrom the group consisting of obesity, increased age, family history ofdiabetes, diabetes during pregnancy, dyslipidemia, high blood pressure,uricemia, insulin resistance, arterial occlusive disease,atherosclerosis, retinopathy, nephropathy, angina pectoris, myocardialinfarction, and stroke.